The present invention relates to cocaine induced sensitization and toxicity, and more specifically to the use of nitric oxide synthase inhibitors in the treatment of cocaine induced sensitization and toxicity in humans.
During the last decade cocaine became the major drug of abuse in the U.S. The powerful addicting properties of the drug result in not only psychosocial misery, but also serious pathophysiological complications that are due to repeated use of the drug. Animal models and human studies have documented the development of severe neurological disorders, such as seizures and brain ischemia with irreversible brain damage following repeated exposure to cocaine. Cocaine related death due to the chronic exposure to cocaine is also documented from animal models and clinical studies.
After repeated doses of cocaine, the body becomes more responsive to the drug so that a dose that was not toxic to a novice user may be toxic or even lethal to an habituated user.
Since there is no successful "antidote" or antagonist or cocaine abuse, the development of therapeutics for the management of cocaine induced toxicities and cocaine craving is a major issue in drug abuse treatment. Several recent studies, including Applicant's publication: Itzhak and Stein, J. Pharmacol. Exp. tHER. 262, 464-470 (1992) suggest the involvement of the glutamatergic system in the effects of cocaine. Particularly, antagonists for the N-methyl-D-aspartate (NMDA) type of glutamate receptors block cocaine induced seizures and lethality in mice. However, the use of NMDA receptor antagonists to treat cocaine-induced toxicities, such as seizures and brain ischemia, may be limited because of the serious side effects of the NMDA receptor antagonists. Although they are considered as neuroprotective agents, MNDA-receptor antagonists cause undesirable psychotomimetic effects.